Aarupfuller7581

Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug target, but conventional TS inhibitors display limited clinical efficacy in refractory or recurrent SCLC. We performed RNA-Seq analysis to identify gene expression changes in SCLC biopsy samples to provide mechanistic insight into the potential utility of targeting pyrimidine biosynthesis to treat SCLC. We identified systematic dysregulation of pyrimidine biosynthesis, including elevated TYMS expression that likely contributes to the lack of efficacy for current TS inhibitors in SCLC. We also identified E2F1-3 upregulation in SCLC as a potential driver of TYMS expression that may contribute to tumor aggressiveness. To test if TS inhibition could be a viable strategy for SCLC treatment, we developed patient-derived organoids (PDOs) from human SCLC biopsy samples and used these to evaluate both conventional fluoropyrimidine drugs (e.g., 5-fluorouracil), platinum-based drugs, and CF10, a novel fluoropyrimidine polymer with enhanced TS inhibition activity. PDOs were relatively resistant to 5-FU and while moderately sensitive to the front-line agent cisplatin, were relatively more sensitive to CF10. Our studies demonstrate dysregulated pyrimidine biosynthesis contributes to drug resistance in SCLC and indicate that a novel approach to target these pathways may improve outcomes.A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.Extracellular vesicles (EVs) are a class of naturally occurring secreted cellular bodies that are involved in long distance cell-to-cell communication. Proteins, lipids, mRNA, and miRNA can be packaged into these vesicles and released from the cell. This information is then delivered to target cells. Since EVs are naturally adapted molecular messengers, they have emerged as an innovative, inexpensive, and robust method to deliver therapeutic cargo in vitro and in vivo. Well-differentiated primary cultures of human airway epithelial cells (HAE) are refractory to standard transfection techniques. Indeed, common strategies used to overexpress or knockdown gene expression in immortalized cell lines simply have no detectable effect in HAE. Here we use EVs to efficiently deliver siRNA or protein to HAE. Furthermore, EVs can deliver CFTR protein to cystic fibrosis donor cells and functionally correct the Cl- channel defect in vitro. EV-mediated delivery of siRNA or proteins to HAE provides a powerful genetic tool in a model system that closely recapitulates the in vivo airways.Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor δ (PPARδ) in cartilage may attenuate the development or progression of OA. PPARδ antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt.% drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. PMX-53 supplier Atomic force microscopy was used to measure the Young's moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy.Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in lower grade gliomas. The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming. However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness. In the present study, by using unbiased transcriptomic profiling, we showed that IDH1 mutations result in substantial changes in the gene sets that govern cellular motility, chemotaxis, and invasion. Mechanistically, rapamycin-insensitive companion of mammalian target of rapamycin (Rictor)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling plays an essential role in the motility and proliferation of IDH1-mutated cells by prompting cytoskeleton reorganization, lamellipodia formation, and enhanced endocytosis. Targeting the Rictor/Rac1 pathway suppresses IDH1-mutated cells by limiting endocytosis and cell proliferation.